This Project combines preclinical work in animals and human post mortem studies to focus on the interaction of the stress system and the noradrenergic (NE) system in the modulation of emotional behavioral and mood disorders. While the NE system has long been implicated in stress responsiveness and in the etiology of depression, we lack some information on the anatomical interface between stress-related and NE- related genes. Thus, describing the interface is one of our first goals. In addition, we plan to study the role of the NE system in mediating individual differences in emotional responsiveness, by relying on a model of spontaneous differences in emotional reactivity in which rats have distinctive patterns of behavior in anxiety-like conditions. Thus, some animals termed high responders (HR) show a great deal of exploration, while others, termed low responders (LR) appear quite timed. These animals with differing emotional predisposition have differing patterns of expression of stress-related genes. We will investigate whether they also exhibit in the expression of NE-related genes in brain circuits implicated in emotional control. We will use chronic, non-habituating stress as a challenge to place demand on the emotional circuitry and study the neurobiological consequences in the NE and stress systems of the HR and LR animals. We will study the possible reversal of these effects by particular classes of anti-depressants (SSRI vs. Noradrenergic drugs_. We will then move to human post- mortem studies to characterize the neuronal phenotype (pattern of expression of relevant genes) of severely depressed individuals versus individually matched controls. While our starting place in this project is the noradrenergic system, we will related our observations to the patterns of expression of stress- and serotonin genes. This work will directly compare the contributions of two critical monoaminergic systems that have been implicated in mood disorders and will link the animal findings to studies in the human brain.